Nu1-acyl-nu1-(5-ethyl-1, 3, 4-thiadiazole-2-yl)-sulfanilamides



Patented Aug. 19, 1958 Free N -ACYL-N -(S-ETHYL-1,3,4-THIADIAZOLE-2-YL)-SULFANILAIVIIDES Russell E. Rhodes, Glenside, and Blaine M. Sutton,Philadelphia, Pa., assignors to Smith, Kline & French Laboratories,Philadelphia, Pa., a corporation of Pennsylvania N Drawing. ApplicationAugust 23, 1956 Serial No. 605,706

7 Claims. (Cl. 260-23935) This invention relates to a new class of N-(5-ethyl- 1,3,4-thiadiazole-2-yl)-sulfanilamide derivatives of unusualtherapeutic properties.

More particularly, this invention relates to N -acyl- N S-ethyl- 1,3,4-thiadiazole-2-yl) -su1fanilamides .represented by the generalstructural formula:

where I R C 0 represents an alkanoyl group. As a practical matter the N-acyl group must be the acyl portion of a nontoxic acid.

The lower saturated alkanoyl (preferably of from 2 to 6 carbon atoms)derivatives are of particular advantage. The alkyl group (R) isadvantageously chosen of low molecular Weight so that the proportion ofactive N -(5-ethyl-l ,3,4-thiadiazole-2-yl) -sulfanilamide released perdosage unit of drug is high, thereby enabling administration of largeamounts of active medicament in a dosage form of convenient size for thepatient. In this regard the compound where R represents methyl is thecompound of choice.

The compounds of this invention have utility as chemotherapeutic agents,particularly as antibacterial agents active against both Gram negativeand Gram positive organisms. Exemplary of such organisms are Micrococcuspyogenes var. aureus, Micrococcus pyogenes var. albus, Streptococcuspyogenes, Diplococcus pneumoniae, Escherichia coli, Aerobacteraerogenes, Proteus vulgaris, and Salmonella typhosa. Further, thesecompounds have particularly favorable characteristics which make themvaluable in medical practice.

N -(5-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is excreted rapidlyfrom the body. This necessitates repeated doses of the drug to provideadequate therapeutic effect. The compounds of this invention have beenfound to give prolonged blood and urine levels of active medicament uponoral administration.

The sulfa family of chemotherapeutic agents is generally accepted to bedetoxified in vivo by acetylation on the N atom. These N compounds areinactive biologically. Contrariwise, the synthetic N -acyl derivativeswhich are the object of this invention are antibacterially active oningestion and give sustained therapeutic blood levels of N-(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide.

It is readily apparent to one skilled in the art that a drug form thatgives prolonged therapeutic blood levels is of great advantage inmedical practice. This unexpected property of the compounds of thisinvention enables the doctor to administer the drug, for example, twicea day rather than at four or six-hour intervals. The great advantage ofsuch a dosage regimen is the security of therapeutic blood levelstwenty-four hours a day with two doses. Another important advantage isconvenience to the patient. A sustained blood level of active medicamentis maintained rather than the peak and valley etfect of the multipledaily administration of current medical practice.

Further, these compounds are quite palatable when compared with thedisagreeable taste of the parent compound, N-(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide. Therefore, the drug maybe administered by preparing suitable pharmaceutical forms, such astablets or suspensions for oral use.

The compounds of this invention are prepared by reacting N-(S-ethyl-l,3,4-thiadiazole-2-yl)-sulfa.nilamide with an acylatingagent, preferably an acid anhydride, in the presence of an inorganic ora tertiary organic base such as pyridine, collidine, tributylamine 'orsodium carbonate in .an inert organic solvent for the sulfanilamide suchas dimethylformamide, water, acetone or a water-acetone mixture,preferably at relatively low temperatures, for instance from 030 C. Itis apparent that the base may be present in equimolar quantities or inexcess. In the latter case, the base may serve as the reaction medium aswell. Since the N -acyl derivatives in solution tend to rearrange to theN atom under the influence of heat, the use of hot solvents during thepreparation of the N -acyl derivatives should be avoided.

The compounds of this invention are also prepared by acylating theN-(S-ethyl-1,3,4-thiadiazole-2-yl)-4-nitrobenzenesulfonamide with anacyl halide or acyl anhydride in an inert organic solvent for thesulfonamide, for example, acetone or dimethylformamide, with conditionswhich may be more forcing than those described previously, such as athigher temperatures, for example, room temperatures to C. Of course thiswider range of reaction conditions, namely using higher temperature andthe more reactive acyl halides, are applicable since the possibility ofN -acylation is not present. The base may be present in equimolarquantities or in excess. In the latter case the base may serve as thereaction medium as well. The resulting N-acyl-N- (S-ethyl- 1,3,4-thiadiazole-2-yD-4-nitrobenzenesulfonamide is reduced under mildreduction conditions to the desired N -acyl-N -(5-ethyl-1,3,4-thiadiazole-Z-yl)-sulfanilamide, for example, by catalytic reductionusing Adams catalyst or palladium-on-charcoal in an alcoholic medium,such as in ethanol or methanol at low pressures and temperatures. Thismethod is particularly advantageous where acylation at the N positionof, N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide is more diflicultdue to RC=O in the foregoing structural formula being a particularlybulky group, such as a tertiary butyryl or benzoyl moiety.

Alternatively, the N -acyl compounds of this invention can be preparedfrom the sodium, potassium or silver salt of N-(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide by reaction with anappropriate acyl halide in an inert organic solvent for thesulfanilamide such as acetone, acetonitrile or dimethylacetamide.

The methods of preparing the compounds of this invention will be readilyapparent from the following examples:

Example I A suspension of 113.6 g. of N-(5-ethyl-1,3,4-thiadiazole-2-y1)-sulfanilamide in a mixture of 1 l. ofacetone and l 1. of water is stirred with 26 ml. of strong ammonia wateruntil a complete solution is attained. The solution is cooled to ()--10C. and 51 g. of acetic anhydride is added rapidly dropwise. After thirtyminutes in the cold, the desired product crystallizes from solution. Theproduct is separated by filtration, washed with Water and cold ethanolto give white crystals of N -acetyl-N -(5-ethyl-1,3,4-thiadiazole-2-y])-sulfanilamide; M. P. 220-221 C. afterpreliminary gathering at 137l38 C. The product may be recrystallizedfrom aqueous acetone if desired.

Example II A suspension of 31.6 g. of the sodium salt of N-(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide (prepared by reactingthe sulfonamide with one equivalent of sodium hydroxide solution,evaporating the water by freeze-drying and using the salt at once) in200 ml. of acetone with 12 ml. of tributylamine is stirred vigorouslywhile 14.0 g. of benzoyl chloride is added dropwise over a two-hourperiod. The crystalline product is obtained by quenching in water andthen Washing the precipitate with water to remove the admixed sodiumchloride. The crude product, N -benzoyl-N-(S-ethyl-1,3,4-thiadiazole-2-yl)- sulfanilamide, is purified byrecrystallization from a benzene dimethylformamide mixture.

Example III A suspension of 32 g. of N-(5-ethyl-1,3,4-thiadiazole-2yl)-4-nitrobenzenesulfonamide in 150 ml. of pyridine is swirled as 13g. of pivalyl chloride is added dropwise. After standing at roomtemperature for twelve hours, the reaction mixture is quenched in alarge excess of water. The crude solid, N-trimethylacetyl-N-(S-ethyl-1,3,4-thiadiazole-2-yl)-4-nitrobenzenesulfonarnide, is then suspended in200 ml. of ethanol with 5% palladium-oncharcoal and hydrogenated at roomtemperature and 50 p. s. i. The resulting solution is then filtered. Thesolid thusly obtained is extracted with acetone. After concentrating thecombined alcohol-acetone filtrates by evaporation under reducedpressure, a crystalline solid, N -trimethylacetyl-N -(S-ethyl-l,3,4-thiadiazole2-yl sulfanilam de, is obtained.

Example IV A suspension of 14.2 g. of N -(5-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide in 50 ml. of acetone is acylated with 6.5 g. ofpropionic anhydride in dimethylformamide with 6 ml. of pyridine at -5 C.The crystalline product, N -propionyl-N-(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide, is obtained byquenching the reaction mixture in water and recrystallizing theprecipitate from aqueous acetone; M. P. 2l9221 C. after preliminarymelting at 9910l C.

Example V A suspension of 26.4 g. of crude oleoyl anhydride (prepared byreacting 29 g. of oleic acid with 15 g. of acetic anhydride and removingthe volatiles in vacuo) and 14.2 g. of N-(-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is reacted according tothe process of Example I-t0 give N -oleoyl-N(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide after trituration Withisooctane in the cold.

Example VI -butyryl-N 5 -ethyll ,3 ,4-thiadiazole-2-yl) -sulfanilamideis prepared from 14.2 g. of N-(5-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide and 7.9 g. of butyricanhydride as in Example I to give white crystals; M. P. 219-221 C. afterpreliminary melting at 120-122 C.

4 Example VII N -phenylacetyl-N-(S-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is prepared from 28.4 g.of N -(5-ethyll,3,4-thiadiazole-Z-yD-sulfanilamide and 25.4 g. ofphenylacetic anhydride as in Example I, but using 4 ml. of pyridine as abase. The crude product is recrystallized from abenzene-dimethylformamide mixture.

Example VIII A solution of 21.4 g. of carbobenzoxyglycyl chloride in dryethyl ether is added dropwise to a stirred suspension of 31.4 g. ofN-(S-ethyl-l,3,4-thiadiaZole-2-yl)-4-nitrobenzenesulfonamide in ml. ofdried ethyl acetate with 9 ml. of pyridine. The reaction mixture isconcentrated in vacuo and cooled. The resulting precipitate is thenseparated, washed with water and dried in vacuo.

The crudeN-carbobenzoxyglycyl-N-(5-ethyl-l,3,4-thiadiazole-Z-yl)-4-nitrobenzenesulfonamideis suspended in 350 m1. of ethanol and hydrogenated at low pressure andtemperature in the presence of palladium black catalyst. The catalyst isseparated by filtration. Concentrating the filtrate and cooling yields awhite solid, N -glycyl-N -(5-ethyl-l,3,4-thiadiazolc-2-yl)-sulfanilamideby fractional crystallization.

Example IX N -isobutyryl-N-(5-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is prepared from 14.2 g.of N -(5-ethy1-l,3,4- thiadiazole-Z-yl)-sulfanilamide and 7.9 g. ofisobutyryl anhydride as in Example I to give white crystals from aqueousacetone, M. P. 21922l C. after preliminary melting at l24125 C.

Example X N -stearoyl-N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamideis prepared from 14.2 g. of N-(5-ethyl-l,3,4-thiadiazole-Z-yl)-sulfanilamide and 27.5 g. of crudestcaric anhydride as in Example V to give white crystals from anisooctane-acetone mixture.

Example XI N -caproyl-N -(5-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamideis prepared from 28.4 g. of N-(5-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide and 21.4 g. of n-caproylanhydride as in Example I but using tributyl amine as the basic reactantto give white crystals from aqueous acetone.

What is claimed is:

is a member selected from the group consisting of saturated alkanoylhaving from 2 to 6 carbon atoms, benzoyl, oleoyl, phcnylacetyl, glycyland stearoyl.

2. Compounds in accordance with claim l characterized in that is acetyl.

3. Compounds in accordance with claim 1 characterized in that ispropionyl.

4. Compounds in accordance with claim 1 characterized in that isbutyryl.

5. Compounds in accordance with claim 1 charactcrized in that RC=O isisobutyryl.

6. Compounds in accordance with claim 1 character- 10 ized in that m -0is caproyl.

7. Compounds in accordance With claim 1 characterized in that R(J=O issaturated alkanoyl having from 2 to 6 carbon atoms.

References Cited in the file of this patent UNITED STATES PATENTS

1. COMPOUNDS REPRESENTED BY THE FOLLOWING FORMULA: